Previous studies from our laboratory have suggested that angiogenesis plays a major role in rheumatoid arthritis (RA). Related studies from our laboratory have indicated that enhanced expression of cyclooxygenase-2 (Cox-2) is also important and parallels the intensity of the inflammatory process and angiogenesis. We have now defined a potential biochemical mechanism that may link these observations. Interleukin-1 (IL-1), which is a powerful stimulator of Cox-2, and prostaglandin E2, which is product of Cox-2, induce the expression of vascular endothelial growth factor (VEGF) in rheumatoid synovial fibroblasts. VEGF expression is upregulated in rheumatoid synovium and probably plays a role in driving angiogenesis. These data may also provide insights into mechanisms by which corticosteroids or nonsteroidal inflammatory drugs regulate inflammatory angiogenesis. These agents have powerful suppressive effects on Cox-2 and prostaglandin E2 production. In addition, corticosteroids suppress interleukin-1 production. Our laboratory is also characterizing cytokine transcription in synovial tissues from patients with early synovitis. Subjects include those with rheumatoid arthritis, reactive arthritis, a various other forms of arthritis. We have noted that the expression of tumor necrosis factor-alpha (TNF- alpha) and IL-1 in virtually all forms of early synovitis. Similarly, gamma interferon expression is common, whereas IL-4 and IL-13 expression is rare. These data suggest that macrophage-derived and type 1 lymphocyte-derived cytokines, in contrast to type 2 cytokines, predominate in early synovitis, regardless of the type of disease. The data suggest the cell-mediated, rather than humoral mechanisms play essential roles in the early stages of the inflammatory process in the joints.